Self antigens on cancers are commonly recognized by the immune system. These antigens are most frequently differentiation antigens, expressed by cancer cells and their normal cell counterparts. It has recently become clear that recognition of these antigens is relevant to immunity to cancer. Prostate-specific membrane antigen (PSMA) is a prostate differentiation antigen. It is a type II glycoprotein with restricted tissue distribution that can be recognized by autoantibodies and T cells of patients with prostate carcinoma. These observations support PSMA as a candidate target for vaccination. It is typically difficult to immunize against self glycoproteins, including differentiation antigens such as PSMA. However we have shown that tolerance against self can be broken by immunization with altered forms of antigen. We will investigate approaches for DNA immunization using self and altered forms of PSMA. Our goals are to: 1) Develop strategies using DNA immunization to induce immunity against PSMA, including immunization with syngeneic DNA, homologous xenogeneic DNA and mutated DNA libraries developed from syngeneic PSMA gene. 2) Investigate whether expansion of dendritic cells in tissue sites (GM-CSF) can enhance DNA immunization. 3) Assess both antibody and T cell responses to mouse PSMA in mouse models. 4) Develop mouse models for trartsplantable syngeneic tumors expressing mouse PSMA and models expressing mouse PSMA in endogenous prostate tumors. 5) Measure tumor immunity and tumor rejection in prevention and established tumor models. 6) Evaluate immunogenicity of DNA immunization with xenogeneic and syngeneic PSMA in a clinical trial in patients with prostate carcinoma.